Certain 4-(1,2,4-oxadiazole-3 or 5-yl) pyridinium salts and derivatives thereof



United States Patent 01 free ABSTRACT OF THE DISCLOSURE Quaternary loweralkoxy(lower) alkyl-1,2,4-oxadiazolylpyridinium salts are describedalong with methods of preparing the same. These compounds showhypoglycemic activity evidenced by their ability to lower blood sugarlevels.

The present application is a continuation-in-part of our applicationSer. No. 676,706 filed Oct. 20, 1967, now abandoned.

PRIOR ART Applicants are aware of British Pat. 875,887 directed topyridinium salts. However the present invention is directed to subjectmatter and utility not disclosed therein.

SUMMARY OF THE INVENTION This invention relates to new quaternary loweralkoxy- (lower)alkyl-1,2,4-oxadiazolylpyridinium salts which may beillustrated by the following formula:

wherein R is lower alkyl, R is lower alkoxy(lower)alkyl, X is apharmaceutically acceptable anion and Z is a trivalent radical selectedfrom the group consisting of and The dotted line represents one doublebond, the position of which is dependent upon the definition of Z. WhenZ is the double bond is between the N and carbon containing R, and whenZ has the other meaning, the double bond is in the other position. Theterms lower alkyl and lower alkoxy include those radicals having 1 to 4carbon atoms.

In general, the compounds are crysaalline solids, soluble in water.

The compounds of the present invention may be prepared by reaction of a1,2,4-oxadiazolylpyridine with a lower alkoxy(lower)alkyl halide at atemperature of to 200 C. with or without a solvent, such as a loweralkyl alcohol, for a time of one minute to twenty-four hours in an openvessel or a sealed bomb.

The reaction is illustrated schematically below:

3,551,437 Patented Dec. 29, 1970 wherein R, R Z and X are ashereinbefore defined.

Among the quaternary compounds of the present inven tion are, forexample: 1-(2-ethoxyethyl)-4-(5-methyl-1,2, 4-oxadiazol 3 yl)pyridiniumchloride, 1-(2-methoxyethyl) -4- (S-methyl-1,2,4-oxadiazol-3 -yl)pyridinium chloride, 1-(2-propoxyethyl) 4 (S-methyl-1,2,4-oxadiazol-3-yl)pyridinium bromide, 1-(2-ethoxymethyl) 4 (5- methyl-1,2,4-oxadiazol3 yl)pyridinium iodide, 1-(2- propoxypropyl) 4(S-methyl-1,2,4-oxadiazol-3-yl)- pyridinium chloride.

The quaternary compounds of the present invention show hypoglycemicactivity which indicates they are use ful as medicaments in the loweringof blood sugar levels. When the quaternary compounds are administeredorally to normal mice, a reduction of blood sugar levels is observed.The compounds of this invention are administered by gavage as salinesolutions to CF1 mice (Carworth Farms, 18-25 grams (4-6 animals).Control animals receive an equivalent volume of saline. Food is withheldfrom animals after dosing. Blood glucose is determined on 0.05 ml.samples of blood by the method of Hotfman [1. Biol. Chem, 120, 51(1937)] as adapted to the Technicon AutoAnalyzer and is expressed aspercent change from predose values. The data are shown in the tablehereinafter. These results show that the compounds of the presentinvention are useful in lowering the blood glucose concentrations ofwarm-blooded animals.

TABLE Decrease in blood glucose in normal mice after oral administrationof 1,2,4-0xadiazolylpyridinium salts Compound--l (2ethoxyethyl)-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridinium chloride:

Dose, mmoles/kg. 3.0 Hours after dosing 3 Percent decrease in bloodglucose 27:4

The products of the present invention as hypoglycemic agents can beincorporated in various pharmaceutical forms such as tablets, capsules,pills and so forth, for immediate or sustained release, by combiningwith suitable carriers. They may be in the form of dosage units for asingle therapeutic dose or in small units for multiple dosages or inlarger units for division into single doses. Obviously, in addition tothe therapeutic hypoglycemic compounds, there may be present excipients,binders, fillers and other therapeutically inert ingredients necessaryin the formulation of the desired pharmaceutical preparation.

DETAILED DESCRIPTION The following examples describe in detail thepreparation of representative quaternary lower alkoxy(lower) alkyl1,2,4-oxadiazolylpyridinium salts of this invention.

EXAM PLE 1 Preparation of 4-(S-methyl-1,2,4-oxadiazol-3-yl)pyridine 'Amixture of 27 g. of isonicotinamidoxime and 50 ml. of acetic anhydrideis warmed on a steam bath for 2 hours, and then heated under reflux for3 hours. The solvent is distilled and the dark liquid residue is dilutedwith water. The crystals which form are collected, washed with water,and recrystallized from ethanol to provide colorless crystals, meltingpoint 92-93 C.

EXAMPLE 2 Preparation ofl-(2-ethoxyethyl)-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridinium chloride Amixture of 5.0 g. of 4-(S-methyl-1,2,4-oxadiazol-3- yl)pyridine and 15ml. of 2-chloroethyl ethyl ether is heated in a bomb at C. for 20 hours.The excess 2-chloroethyl ether is evaporated and the black residue isrecrystallized from isopropyl alcohol-ether to give offwhite crystals,melting point l87188 C.

EXAMPLE 3 Preparation of 4-(5-ethyl-l,2,4-oxadiazol-3-yl)pyridine Amixture of 27 g. of isonicotinamidoxime and 60 ml. of propionicanhydride is warmed on a steam bath for 2 hours and then heated at 145C. for 4 hours. The solvent is distilled and the dark liquid residue isdiluted with water. The crystals which form are collected, washed withwater, and recrystallized from petroleum ether to provide colorlesscrystals, melting point 42-44" C.

EXAMPLE 4 Preparation of l-(3-propoxypropyl)-4-(5-ethyl-1,2,4-oxadiaZol-3-yl)pyridinium chloride A mixture of 5.0 g. of4-(5-ethyl-l,2,4-oxadiazol-3-yl) pyridine and 15 ml. of 3-chloropropylpropyl ether is heated in a bomb at 130 C. for 20 hours. The excess 3-chloropropyl ether is evaporated and the residue is recrystallized togive the product of the example.

We claim:

1. A quaternary oxadiazolylpyridinium salt of the wherein R is loweralkyl, R is lower alkoxy(lower)alkyl, X is a pharmaceutically acceptableanion, Z is a trivalent radical selected from the group consisting ofand References Cited FOREIGN PATENTS 875,887 8/l96l Great Britain 260296ALAN L. ROTMAN, Primary Examiner US. Cl. X.R. 260999

